In the following discussion, a number of citations from professional journals are included for the convenience of the reader. These citations are in abbreviated form in the text by author and year only. The full citation of each is set forth in the References section at the end of the specification. While these citations more fully describe the state of the art to which the present invention pertains, the inclusion of these citations is not intended to be an admission that any of the cited publications represent prior art with respect to the present invention.
By a large margin, malaria is the most prevalent disease in the world. It is estimated for the year 1986 that some 489 million people contracted malaria, 2.3 million of whom died from the disease (Sturchler, 1989). Whereas effective antimalarial drugs exist, drug-resistance, particularly resistance to chloroquine (CQ), the most useful antimalarial drug, has become an enormous problem (Payne, 1987).
Quinoline antimalarials such as quinine, mefloquine, and amodiaquine are active to various extents against CQ-resistant malaria (Geary and Jensen, 1983; Geary et al., 1987; Knowles et al., 1984; Watkins et al., 1984; Cowman and Foote, 1990; Sowunmi et al., 1990). Although Cowman and Foote (1990) suggest that CQ resistance may dispose the parasite to resistance to other quinolines, LeBras et al. (1983), Schmidt et al. (1977), Geary and Jensen (1983) and Oduola et. al. (1988) observe a significant lack of cross-resistance among quinoline-containing antimalarials.
It is an object of this invention to provide a new class of quinolines which are active against malaria and, in particular, CQ resistant malaria. The compounds of this invention are bisquinolines.
Many prior art bisquinolines have been reported to be inactive against malaria. These include the succinic acid diester of amodiaquine as a potential repository form (Elslager et al, 1969), and bisquinolines lacking either a 4-amino function or with a bridge at the 3 rather than the 4-position (Nasr et al, 1979; Nasr et al, 1978).
Examples of bisquinolines which have been reported to be active against malaria include several bisquinolylpiperazines such as piperaquine, hydroxypiperaquine, dichloroquinazine, 12494RP (Benazet, 1965; 1967; Lafaix et al., 1967; LeBras et al., 1983; Li et al., 1981a; 1981b; 1984; Zhang et al., 1987; Li and Huang, 1988; Chen et al, 1982), and 1,4-bis(7-chloro-4-quinolyl-amino)piperazine (Singh et al., 1971). In general, these bisquinolines are more potent than CQ, and are active against CQ-resistant malaria. Both piperaquine (PQ) and hydroxypiperaquine are claimed to be very effective against CQ-resistant malaria in China (Chen et al., 1982; Li et al., 1981b; 1984; Li and Huang, 1988). Each of these drugs also has a longer duration of action, and less toxicity when compared to CQ (Li et al., 1981a; Lin et. al., 1982). Dichloroquinazine is active against CQ-resistant falciparum malaria (LeBras et al., 1983), and a mixture of 12,494RP and dichloroquinazine is clinically effective against falciparum malaria and exerts a suppressive effect lasting for 3 weeks (Lafaix et al. 1967; Benazet, 1965). Resistance to dichloroquinazine, however, is noted for a CQ-resistant strain of P. berghei (Warhurst, 1966). Although 1,4-bis(7-chloro-4-quinolylamino)piperazine has not been screened against CQ-resistant malaria, it is significantly more effective than is CQ against P. berghei in mice (Singh et al., 1971).
This invention relates to a new class of bis-4-aminoquinoline antimalarial agents. These agents exhibit potent activity against CQ-resistant malaria in the in vitro and in vivo tests hereinafter described.